What exactly causes proteins to take different secondary structures

[betterfuture]

Okay. There was a question which I was stumped on regarding protein structures.

The primary structure determines the function of the protein. And so it should also have the same secondary structure, right?

Because a question came up and stated in a passage discussing a regular form of a protein and an abnormal form of a protein. They both had the same primary structure, but they differed in how they folded. The normal protein consists entirely of alpha helices. The abnormal consists of a mixture of alpha helices and beta sheet. If they both have the same linear structure, same sequence of amino acids, how in the world do they take up different secondary structures? Is it the environment or something? Am I thinking way too much into this because maybe the answer is straightforward but I can't think right now. Help

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[yeasureyoubetcha]

Okay. There was a question which I was stumped on regarding protein structures.

The primary structure determines the function of the protein. And so it should also have the same secondary structure, right?

Because a question came up and stated in a passage discussing a regular form of a protein and an abnormal form of a protein. They both had the same primary structure, but they differed in how they folded. The normal protein consists entirely of alpha helices. The abnormal consists of a mixture of alpha helices and beta sheet. If they both have the same linear structure, same sequence of amino acids, how in the world do they take up different secondary structures? Is it the environment or something? Am I thinking way too much into this because maybe the answer is straightforward but I can't think right now. Help

Could be any of the following: Environment, misfolding due to chaperone proteins, prion proteins...can you post the actual passage and question?

 

[betterfuture]

@yeasureyoubetcha I am still kind of new to this forum. How exactly do you put up an attachment, like an image to the passage?

 

[yeasureyoubetcha]

@yeasureyoubetcha I am still kind of new to this forum. How exactly do you put up an attachment, like an image to the passage?

I've never had to do it, but try taking a screenshot/screenshots of what you're looking at for us using ctrl+PrtSc and do what you will with it in paint or whatever. Then upload it

 

[betterfuture]

 

[yeasureyoubetcha]

View attachment 201976

So the thing to remember here is that this is an infectious protein. The normal Prp is a protein that for some reason or another misfolds or loses structure incredibly easily. The PrpSc that it becomes possesses some kind of chaperone capabilities, but when it comes into contact with normal Prp, it causes the same misfolding that created it.

 

[betterfuture]

So the passage doesn't state exactly state what causes the PrPsc protein to form different secondary structures, right?

 

[yeasureyoubetcha]

So the passage doesn't state exactly state what causes the PrPsc protein to form different secondary structures, right?

No, it might be one of those things they just assume you've come across in content review. Some passages you wont even need to read much of

 

[betterfuture]

I don't think I am understanding what you are telling me. They have the same linear sequence of amino acids. Secondary structures arise from linear structure of amino acids. And as for chaperon proteins, they assist in the folding of proteins which occurs in tertiary structures. Chaperones don't assist in secondary structures.

 

[yeasureyoubetcha]

I don't think I am understanding what you are telling me. They have the same linear sequence of amino acids. Secondary structures arise from linear structure of amino acids. And as for chaperon proteins, they assist in the folding of proteins which occurs in tertiary structures. Chaperones don't assist in secondary structures.

Wasn't saying it was a chaperone. Its could act like a chaperone. Its still one of those things we don't have a lot of info on.

 

[aldol16]

I love this question. This is what basic research is about now in computational biochemistry, namely how do you get multiple secondary structures from one sequence and how could you predict that computationally? The answer is that sometimes in protein folding, there are deep local minima in the potential energy surface and so a structure can get "stuck" there and never have enough energy to come back out. That's the basis of prion disease. Or, as others have mentioned, there could be a defective chaperone or degradation (ubiquitin) system so that the misfolded form is no longer degraded as it should be and sticks around.

 

[Romz]

You're having trouble with this question because your assumption that primary structure determines function is wrong. From how I learned it in school, protein activity is a function of it's tertiary structure. As @aldol16 has mentioned, you cannot predict the tertiary structure of the protein from it's primary sequence (you can predict the secondary structure from primary sequence, but we're getting ahead of ourselves). In a disease like PrPsc, the tertiary structure of the protein is modified via modification of the secondary structure from strictly alpha helices --> alpha helices + beta sheets (as denoted in your passage). Hence, we observe a pathological change in protein function. As the other posters have mentioned, there can be a plethora of reasons as to how secondary structure can be modified. (Most likely due to a change in electrostatic interactions between amino acids caused by exogenous PrPsc presence i.e. eating contaminated meat).

 

[betterfuture]

you cannot predict the tertiary structure of the protein from it's primary sequence (you can predict the secondary structure from primary sequence, but we're getting ahead of ourselves).

Then what exactly does this mean?

Thanks to the proliferation of protein and nucleic acid sequences that are catalogued in genome databases, the function of a gene—and its encoded protein—can often be predicted by simply comparing its sequence with those of previously characterized genes. Because amino acid sequence determines protein structure and structure dictates biochemical function, proteins that share a similar amino acid sequence usually perform similar biochemical functions, even when they are found in distantly related organisms. At present, determining what a newly discovered protein does therefore usually begins with a search for previously identified proteins that are similar in their amino acid sequences.

Source:http://www.ncbi.nlm.nih.gov/books/NBK26820/#A1604​

 

[aldol16]

Then what exactly does this mean?

Thanks to the proliferation of protein and nucleic acid sequences that are catalogued in genome databases, the function of a gene—and its encoded protein—can often be predicted by simply comparing its sequence with those of previously characterized genes. Because amino acid sequence determines protein structure and structure dictates biochemical function, proteins that share a similar amino acid sequence usually perform similar biochemical functions, even when they are found in distantly related organisms. At present, determining what a newly discovered protein does therefore usually begins with a search for previously identified proteins that are similar in their amino acid sequences.

Source:http://www.ncbi.nlm.nih.gov/books/NBK26820/#A1604

So what that is talking about is knowledge-based computational modeling of a protein. This may be a surprise to you, but even now, we cannot predict protein folding. There are generally two camps when it comes to protein folding - the quantum mechanical camp, in which the computer performs iterations of the Schrodinger equation, and the knowledge-based camp, in which you take a sequence, align a fragment of some length to a similar one in the PDB, and then predict based on the PDB statistics whether similar sequences fold into alpha helices, beta sheets, or random coils. The advantage of the first one is that it gives you a very good representation of the energy landscape. The problem is, the Schrodinger equation cannot be solved exactly for any atom larger than hydrogen. So the computer has to represent each atom in 3D space and do a calculation of the energy, move an atom, do another calculation, etc. until it reaches the global minimum. Here, you have to be wary of saddle points as well. That's why knowledge-based models were developed - if some sequence exists in the PDB 90% of the time as alpha helix and 10% of the time as random coil, that model would tell you that a similar sequence exists as an alpha helix. The pros of this approach is that you can bypass a lot of computation and predict with some confidence that your sequence takes a particular secondary structure. The big cons are that 1) structures in the PDB may not be representative since they are inherently limited only to those that can be crystallized and 2) you can't predict any new, unseen secondary structure.

So the take-away is that in this day and age, we still do not have the tools available to completely calculate structure from sequence - that's a goal that we want to be able to achieve in the near future with ever-increasing computing power, but as of now, it's still not possible except for the smallest proteins.

 

[Astra]

So what that is talking about is knowledge-based computational modeling of a protein. This may be a surprise to you, but even now, we cannot predict protein folding. There are generally two camps when it comes to protein folding - the quantum mechanical camp, in which the computer performs iterations of the Schrodinger equation, and the knowledge-based camp, in which you take a sequence, align a fragment of some length to a similar one in the PDB, and then predict based on the PDB statistics whether similar sequences fold into alpha helices, beta sheets, or random coils. The advantage of the first one is that it gives you a very good representation of the energy landscape. The problem is, the Schrodinger equation cannot be solved exactly for any atom larger than hydrogen. So the computer has to represent each atom in 3D space and do a calculation of the energy, move an atom, do another calculation, etc. until it reaches the global minimum. Here, you have to be wary of saddle points as well. That's why knowledge-based models were developed - if some sequence exists in the PDB 90% of the time as alpha helix and 10% of the time as random coil, that model would tell you that a similar sequence exists as an alpha helix. The pros of this approach is that you can bypass a lot of computation and predict with some confidence that your sequence takes a particular secondary structure. The big cons are that 1) structures in the PDB may not be representative since they are inherently limited only to those that can be crystallized and 2) you can't predict any new, unseen secondary structure.

So the take-away is that in this day and age, we still do not have the tools available to completely calculate structure from sequence - that's a goal that we want to be able to achieve in the near future with ever-increasing computing power, but as of now, it's still not possible except for the smallest proteins.

something about this is so unsettling and awe inspiring.

We can know the structure of something but cannot model how it will behave even though it is found with us.

 

[betterfuture]

So what can we safely assume about the primary and secondary structures of proteins? I don't want to get into the complex stuff.

 

[aldol16]

So what can we safely assume about the primary and secondary structures of proteins? I don't want to get into the complex stuff.

Primary sequence cannot reliably predict secondary structure, and if you can't predict secondary structure, you can't predict anything after it either.

 

[betterfuture]

Primary sequence cannot reliably predict secondary structure, and if you can't predict secondary structure, you can't predict anything after it either.

For the MCAT, I mean.

 

[aldol16]

For the MCAT, I mean.

I don't think I can reduce it to anything less than that...

 

[Astra]

So what can we safely assume about the primary and secondary structures of proteins? I don't want to get into the complex stuff.

Primary structure determined by sequence of amino acids.

Secondary structure formed by hydrogen bonds between amino acids of the same chain, 2 types, alpha and beta chains.

Proline introduces kinks into alpha helices and is not often found in alpha helices.

Glycine is too flexible for alpha helices and causes the chain to have a slightly different shape.

As for the MCAT, they will probably will give you a short sequence and ask what it might be from and these should be sufficient

 

[betterfuture]

Proline is not found in alpha helices? What? Seriously. Kaplan states it found at the start of alpha helices.

 

[Astra]

Proline is not found in alpha helices? What? Seriously. Kaplan states it found at the start of alpha helices.

More specifically yea its found there, but it is not found in the turns

 

[aldol16]

Proline is not found in alpha helices? What? Seriously. Kaplan states it found at the start of alpha helices.

Instead of just memorizing where proline is found, know the structure and use that to reason out where you would expect it.

 

[betterfuture]

More specifically yea its found there, but it is not found in the turns

Proline found at start of alpha helices and found in turns of beta sheets.

 

[betterfuture]

Instead of just memorizing where proline is found, know the structure and use that to reason out where you would expect it.

Trying to get there.